Hypoglycemia (i.e. abnormally low blood glucose levels) is believed to be the cause of death in about three percent of insulin-treated diabetic patients. The putative mechanism for death due to hypoglycemia is a hypoglycemia-induced prolongation of the QT interval of the intracardiac electrogram (IEGM), which increases the risk of malignant ventricular tachycardia. See, for example, Eckert et al., “Hypoglycemia Leads to an Increased QT Interval in Normal Men,” Clinical Physiology. 1998. Volume 18, Issue 6, Page 570 and Heller, “Abnormalities of the Electrocardiogram during Hypoglycaemia: The Cause of the Dead in Bed Syndrome,” Int. J. Clin. Pract. Suppl. 2002 July; (129): 27-32. Note that QT interval represents the portion of the IEGM between the beginning of ventricular depolarization and the end of ventricular repolarization. Ventricular depolarization is manifest within the IEGM as a QRS complex (also referred to as an R-wave.) The QRS complex usually follows an atrial depolarization (also referred to as a P-wave.) Ventricular repolarization is manifest within the IEGM as a T-wave. Strictly speaking, P-waves, R-waves and T-waves are features of a surface electrocardiogram (ECG). For convenience and generality, the terms R-wave, T-wave and P-wave are used herein (and in the literature) to refer to the corresponding internal signal components as well.
In adults, if not treated properly, severe hypoglycemia may result in coma and irreversible brain damage. McCarthy et al., “Mild hypoglycemia and impairment of brain stem and cortical evoked potentials in healthy subjects.” Department of Pediatrics, Yale University School of Medicine, New Haven, Conn. 06510.
Even in cases where hypoglycemia does not cause severe consequences, it is often the limiting factor in achieving good glycemic control in patients with diabetes, particular insulin-depended diabetics. In this regard, patients sometimes refrain from taking prescribed dosages of insulin for fear that the insulin might trigger an episode of hypoglycemia, which can be unpleasant. Failure to take the prescribed insulin prevents the patient from maintaining glycemic levels within a healthy range, thus often leading to additional health problems.
Hypoglycemia is also a serious and frequent problem in patients suffering hyperinsulinism, wherein the body generates too much insulin, thereby triggering episodes of hypoglycemia even if an otherwise sufficient amount of sugar or other glucose-generating substances are ingested. Medications appropriate for addressing hyperinsulinism includes sulfonylureas, meglitinides, biguanides, thiazolidinediones, or alpha glucosidase inhibitors.
In view of the adverse consequences of hypoglycemia, particularly within insulin-dependent diabetic patients, it is highly desirable to provide techniques for detecting hypoglycemia within such patients and automatically delivering appropriate therapy or warning signals. It is known that hypoglycemia can be detected based on observation of changes in the QT interval observed within an ECG, as well as based on observation of dispersion of QT intervals within the ECG (based on studies involving experimental hypoglycemia within adults with type 1 diabetes, i.e. diabetes wherein the body does not make insulin or at least doe not make enough insulin.) Studies in diabetics have also shown that hypoglycemia can be detected based on observation of a significant lengthening of the QTc interval occurring during spontaneous nocturnal hypoglycemia. See, Robinson et al., “Changes In Cardiac Repolarization During Clinical Episodes Of Nocturnal Hypoglycaemia In Adults With Type 1 Diabetes” Diabetologia. 2004 February;47(2):312-5. Epub 2004 Jan. 08. The QTc interval is an adjusted version of the QT interval that has been corrected to a heart rate of 60 beats per minute (bpm). See, also, U.S. Pat. No. 6,572,542 to Houben, et al., entitled “System and Method for Monitoring and Controlling the Glycemic State of A Patient,” which describes a technique exploiting a combination of ECG signals and electroencephalogram (EEG) for the detection of hypoglycemia.
Accordingly, various techniques have been developed for detecting hypoglycemia based on ECG signals. However, it would also be desirable to provide techniques for detecting hypoglycemia based on IEGM signals so that detection may be performed by an implantable medical device without requiring surface electrodes. In particular, it is desirable to provide techniques for detecting hypoglycemia (or for detecting blood glucose levels so that hypoglycemia may be detected therefrom) for use with pacemakers or ICDs, as many patients at risk of hypoglycemia are also candidates for pacemakers and/or ICDs and such devices routinely detect the IEGM for use in pacing the heart and detecting arrhythmias
One effective technique for detecting blood glucose levels based on IEGM signals sensed by an implantable medical device is set forth in U.S. Patent Application Serial No. 2004/0077962 of Kroll, published Apr. 22, 2004, entitled “System and Method for Monitoring Blood Glucose Levels Using an Implantable Medical Device.” Briefly, with the technique of Kroll, blood glucose levels are determined by an implantable device based on IEGM signals by detecting and examine a combination of T-wave amplitude fraction and QTc interval. The technique may also be used to detect hypoglycemia based on changes in blood glucose levels. See also U.S. Pat. No. 5,741,211 to Renirie, entitled “System And Method For Continuous Monitoring Of Diabetes-Related Blood Constituents.” Renirie is primarily directed to a Holter-type external monitor, but has some speculative discussions pertaining to implantable devices as well.
Another effective technique for use with implantable devices is set forth in U.S. patent application Serial No. 11/043,612, of Kil et al., filed Jan. 25, 2005, now U.S. Pat. No. 7,502,644 entitled “System And Method For Distinguishing Among Cardiac Ischemia, Hypoglycemia And Hyperglycemia Using An Implantable Medical Device”. Briefly, techniques are described therein for detecting and distinguishing ischemia, hypoglycemia and hyperglycemia based on IEGM signals. Ischemia is detected based on a shortening of the interval between the QRS complex and the end of a T-wave (QTmax), alone or in combination with a change in ST segment elevation, which is the relative elevation of the portion of the cardiac signal between the end of the QRS-complex and the beginning of the T-wave. Alternatively, ischemia is detected based on a change in ST segment elevation combined with minimal change in the interval between the QRS complex and the end of the T-wave (QTend). Hypoglycemia is detected based on a change in ST segment elevation along with a lengthening of either QTmax or QTend. Hyperglycemia is detected based on a change in ST segment elevation along with minimal change in QTmax and in QTend. By exploiting QTmax and QTend in combination with ST segment elevation, changes in ST segment elevation caused by hypo/hyperglycemia can be properly distinguished from changes caused by ischemia.
Although the techniques of Kroll and Kil et al. are effective, it would be desirable to provide still other techniques for detecting hypoglycemia using an implantable device and it is to that end that aspects of the present invention are directed. It is particularly important to provide techniques for detecting hypoglycemia during paced beats rather than sensed beats as many patients with diabetes also have cardiac abnormalities requiring frequent pacing. Techniques based on an examination of the QRS complex are typically not effective in the case of paced beats since the QRS complex is replaced with an evoked response having a generally different shape. Accordingly, aspects of the invention are also directed to providing techniques for detecting hypoglycemia based on paced beats. Moreover, still other aspects of the invention are directed to providing techniques for tracking changes in glycemic state so as to allow patients to achieve improved glycemic control. In particular, it is desirable to provide techniques for predicting the onset of an episode of hypoglycemia in advance so as to warn the patient and still other aspects of the invention are directed to that end.